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2018 ; 9
(ä): 508
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Downregulation of SLC7A7 Triggers an Inflammatory Phenotype in Human Macrophages
and Airway Epithelial Cells
#MMPMID29616026
Rotoli BM
; Barilli A
; Visigalli R
; Ingoglia F
; Milioli M
; Di Lascia M
; Riccardi B
; Puccini P
; Dall'Asta V
Front Immunol
2018[]; 9
(ä): 508
PMID29616026
show ga
Lysinuric protein intolerance (LPI) is a recessively inherited aminoaciduria
caused by mutations of SLC7A7, the gene encoding y+LAT1 light chain of system
y(+)L for cationic amino acid transport. The pathogenesis of LPI is still
unknown. In this study, we have utilized a gene silencing approach in macrophages
and airway epithelial cells to investigate whether complications affecting lung
and immune system are directly ascribable to the lack of SLC7A7 or, rather,
mediated by an abnormal accumulation of arginine in mutated cells. When
SLC7A7/y+LAT1 was silenced in human THP-1 macrophages and A549 airway epithelial
cells by means of short interference RNA (siRNA), a significant induction of the
expression and release of the inflammatory mediators IL1? and TNF? was observed,
no matter the intracellular arginine availability. This effect was mainly
regulated at transcriptional level through the activation of NF?B signaling
pathway. Moreover, since respiratory epithelial cells are the important sources
of chemokines in response to pro-inflammatory stimuli, the effect of IL1? has
been addressed on SLC7A7 silenced A549 cells. Results obtained indicated that the
downregulation of SLC7A7/y+LAT1 markedly strengthened the stimulatory effect of
the cytokine on CCL5/RANTES expression and release without affecting the levels
of CXCL8/IL8. Consistently, also the conditioned medium of silenced THP-1
macrophages activated airway epithelial cells in terms of CCL5/RANTES expression
due to the presence of elevated amount of proinflammatory cytokines. In
conclusion, our results point to a novel thus far unknown function of
SLC7A7/y+LAT1, that, under physiological conditions, besides transporting
arginine, may act as a brake to restrain inflammation.